ClinVar Miner

Submissions for variant NM_004281.3(BAG3):c.872C>T (p.Ser291Leu) (rs368866313)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037902 SCV000061564 uncertain significance not specified 2013-03-04 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Ser291Leu varia nt in BAG3 has not been reported in the literature nor previously identified by our laboratory. This variant has been identified in 3/8600 European American chr omosomes from a broad population by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS). Serine (Ser) at position 291 is not conserved in mamm als and one species (rock hyrax) carries a leucine (Leu; this variant), raising the possibility that this change may be tolerated. In addition, other computatio nal analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may not impact the protein, though this information i s not predictive enough to rule out pathogenicity. Although this data supports t hat the Ser291Leu variant may be benign, additional studies are needed to fully assess its clinical significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726747 SCV000702729 uncertain significance not provided 2016-11-16 criteria provided, single submitter clinical testing
Invitae RCV000822800 SCV000963617 uncertain significance Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 291 of the BAG3 protein (p.Ser291Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs368866313, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with BAG3-related disease. ClinVar contains an entry for this variant (Variation ID: 44792). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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